Georgia Papavasiliou - Academia.edu (original) (raw)

Papers by Georgia Papavasiliou

Biomacromolecules, Nov 30, 2020

In the early 1940s, Paul Flory and John Rehner published a series of papers on the properties of ... more In the early 1940s, Paul Flory and John Rehner published a series of papers on the properties of swellable polymeric networks. Originally intended for vulcanized rubber, their development has since been extensively used and extended to much more complex systems, such as hydrogels, and used to estimate the mesh size of such networks. In this article, we take a look at the development of the Flory−Rehner equation and highlight several issues that arise when using such a theory for the described hydrogel networks. We then propose a new approach and equations to accurately calculate the backbone molecular weight in-between crosslinks while explicitly accounting for the molecular mass of the crosslinker and branch segments. The approach also provides more applicable mesh dimensions, for complex networks with macromeric crosslinkers and/or a high degree of branching, as is the case of biocompatible hydrogels. The approach is finally illustrated by a case study comparing the values obtained with our proposed approach to those using the state-of-the-art approach.

Nanotechnology, Science and Applications, Apr 1, 2022

Background: Rotational manipulation of chains or clusters of magnetic nanoparticles (MNPs) offers... more Background: Rotational manipulation of chains or clusters of magnetic nanoparticles (MNPs) offers a means for directed translation and payload delivery that should be explored for clinical use. Multiple MNP types are available, yet few studies have performed sideby-side comparisons to evaluate characteristics such as velocity, movement at a distance, and capacity for drug conveyance or dispersion. Purpose: Our goal was to design, build, and study an electric device allowing simultaneous, multichannel testing (e.g., racing) of MNPs in response to a rotating magnetic field. We would then select the "best" MNP and use it with optimized device settings, to transport an unbound therapeutic agent. Methods: A magnetomotive system was constructed, with a Helmholtz pair of coils on either side of a single perpendicular coil, on top of which was placed an acrylic tray having multiple parallel lanes. Five different MNPs were tested: graphene-coated cobalt MNPs (TurboBeads™), nickel nanorods, gold-iron alloy MNPs, gold-coated Fe 3 O 4 MNPs, and uncoated Fe 3 O 4 MNPs. Velocities were determined in response to varying magnetic field frequencies (5-200 Hz) and heights (0-18 cm). Velocities were normalized to account for minor lane differences. Doxorubicin was chosen as the therapeutic agent, assayed using a CLARIOstar Plus microplate reader. Results: The MMS generated a maximal MNP velocity of 0.9 cm/s. All MNPs encountered a "critical" frequency at 20-30 Hz. Nickel nanorods had the optimal response based on tray height and were then shown to enable unbound doxorubicin dispersion along 10.5 cm in <30 sec. Conclusion: A rotating magnetic field can be conveniently generated using a three-coil electromagnetic device, and used to induce rotational and translational movement of MNP aggregates over mesoscale distances. The responses of various MNPs can be compared side-by-side using multichannel acrylic trays to assess suitability for drug delivery, highlighting their potential for further in vivo applications.

Biomacromolecules, Mar 17, 2023

In the early 1940s, Paul Flory and John Rehner published a series of papers on the properties of ... more In the early 1940s, Paul Flory and John Rehner published a series of papers on the properties of swellable polymeric networks. Originally intended for vulcanized rubber, their development has since been extensively used and extended to much more complex systems, such as hydrogels, and used to estimate the mesh size of such networks. In this article, we take a look at the development of the Flory−Rehner equation and highlight several issues that arise when using such a theory for the described hydrogel networks. We then propose a new approach and equations to accurately calculate the backbone molecular weight in-between crosslinks while explicitly accounting for the molecular mass of the crosslinker and branch segments. The approach also provides more applicable mesh dimensions, for complex networks with macromeric crosslinkers and/or a high degree of branching, as is the case of biocompatible hydrogels. The approach is finally illustrated by a case study comparing the values obtained with our proposed approach to those using the state-of-the-art approach.

Macromolecular Reaction Engineering, May 17, 2018

N-vinyl pyrrolidone (NVP) aqueous-phase polymerization is known to depend on the degree of hydrat... more N-vinyl pyrrolidone (NVP) aqueous-phase polymerization is known to depend on the degree of hydration of the NVP molecules, resulting in an increase in the rate of propagation with decreasing monomer concentration. When potassium monophosphate and sodium hexametaphosphate are added to the monomer solution the reaction kinetics slow down, with the degree of retardation being dependent on salt-to-monomer concentration ratio. Using polymerization reaction models in combination with ion coordination theory, this effect can be associated with an active interaction of the ions in solution with the NVP molecules. When varying the solution pH, an optimum operating zone ranging approximately from pH 4 to pH 7 for the NVP-V-50 2,2′-Azobis(2-methylpropionamidine) dihydrochloride (AAPH) system is found. Potassium persulfate is unable to initiate NVP homopolymerization. The addition of poly(ethylene glycol) diacrylate as a comonomer reduces the kinetic slowdown caused by the addition of salts or by extreme pH and significantly increases the overall conversion rate.

Journal of Biomedical Optics, Nov 8, 2019

Lymph node biopsy is a primary means of staging breast cancer, yet standard pathological techniqu... more Lymph node biopsy is a primary means of staging breast cancer, yet standard pathological techniques are time-consuming and typically sample less than 1% of the total node volume. A low-cost fluorescence optical projection tomography (OPT) protocol is demonstrated for rapid imaging of whole lymph nodes in three dimensions. The relatively low scattering properties of lymph node tissue can be leveraged to significantly improve spatial resolution of lymph node OPT by employing angular restriction of photon detection. It is demonstrated through porcine lymph node metastases models that simple filtered-backprojection reconstruction is sufficient to detect and localize 200-μm-diameter metastases (the smallest clinically significant) in 1-cm-diameter lymph nodes. © The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

Macromolecular Reaction Engineering, Nov 15, 2013

PEGDA hydrogels copolymerized with NVP using free‐radical photopolymerization are used in biomedi... more PEGDA hydrogels copolymerized with NVP using free‐radical photopolymerization are used in biomedical applications. These networks consist of a poly(acrylate‐co‐vinyl pyrrolidone) backbone crosslinked with PEG chains whose crosslink density is dependent on the backbone molecular weight and composition. Insight into the network structure and characterization of the backbone molecular weight and composition is achieved by considering hydrogel degradation through ester bond hydrolysis resulting in the release of PEG and poly(acrylic acid‐co‐vinyl pyrrolidone). A model is developed to determine the influence of kinetic constants and phenomena on the backbone formation and is compared to experimental data. Results indicate that the backbone molecular weight is related to the amount of NVP and unaffected by polymerization time.

Acta Biomaterialia, Jul 1, 2012

Controlled scaffold degradation is a critical design criterion for the clinical success of tissue... more Controlled scaffold degradation is a critical design criterion for the clinical success of tissue engineered constructs. Here, we exploited a biomimetic poly(ethylene glycol) diacrylate (PEGDA) hydrogel system immobilized with tethered YRGDS as the cell adhesion ligand and with either single (SSite) or multiple (MSite) collagenase-sensitive domains between crosslinks, to systematically study the effect of proteolytic cleavage site presentation on hydrogel degradation rate and 3D fibroblast invasion in vitro. Through the incorporation of multiple collagenasesensitive domains between crosslinks, hydrogel degradation rate was controlled and enhanced independent of alterations in compressive modulus. As compared to SSite hydrogels, MSite hydrogels resulted in increased 3D fibroblast invasion in vitro which occurred over a wider range of compressive modulus. Furthermore, encapsulated soluble acidic fibroblast growth factor (FGF-1), a potent mitogen during processes such as vascularization and wound healing, was incorporated into SSite and MSite PEGDA scaffolds to determine its in vitro potential on fibroblast cell invasion. Hydrogels containing soluble FGF-1 significantly enhanced 3D fibroblast invasion in a dose-dependent manner within the different types of PEG matrices investigated over a period of 15 days. The methodology presented provides flexibility in designing PEG scaffolds with desired mechanical properties, but with increased susceptibility to proteolytically-mediated degradation. These results indicate that effective tuning of initial matrix stiffness and hydrogel degradation kinetics plays a critical role in effectively designing PEG scaffolds that promote controlled 3D cellular behavior and in situ tissue regeneration.

Biomaterials Science, Jul 7, 2014

Controlled vascular response in scaffolds following implantation remains a significant clinical c... more Controlled vascular response in scaffolds following implantation remains a significant clinical challenge. A critical biomaterial design criterion is the synchronization of the rates of scaffold degradation and vascularized tissue formation. Matrix metalloproteinases (MMPs) are key enzymes that regulate neovascularization and extracellular matrix remodelling. Synthetic proteasesensitive hydrogels offer controllable environments for investigating the role of matrix degradation on neovascularization. In this study, PEG hydrogels containing MMP-sensitive peptides with increased catalytic activity for MMPs expressed during neovascularization were investigated. Scaffolds were functionalized with MMP-2-, MMP-14-or general collagenase-sensitive peptides and with varying peptide concentration using crosslinkers containing one (SSite) or multiple (TSite) repeats of each protease-sensitive sequence. Increasing peptide concentration enhanced the degradation kinetics of scaffolds functionalized with MMP-specific sequences while 80% of the collagenase-sensitive scaffolds remained upon exposure to MMP-2 and MMP-14. In vitro neovascularization was consistent with in vivo tissue invasion with significantly increased invasion occurring within SSite MMP-specific as compared to collagenase-sensitive hydrogels and with further invasion in TSite as compared to SSite hydrogels regardless of peptide specificity. All scaffolds supported in vivo neovascularization; however, this was not dependent on peptide specificity. These findings demonstrate that peptide concentration and specificity regulate in vivo scaffold degradation, neovascularization and matrix remodelling.

Tissue Engineering Part A, Dec 1, 2012

The volume of tissue that can be engineered is limited by the extent to which vascularization can... more The volume of tissue that can be engineered is limited by the extent to which vascularization can be stimulated within the scaffold. The ability of a scaffold to induce vascularization is highly dependent on its rate of degradation. We present a novel approach for engineering poly (ethylene glycol) diacrylate (PEGDA) hydrogels with controlled protease-mediated degradation independent of alterations in hydrogel mechanical and physical properties. Matrix metalloproteinase (MMP)-sensitive peptides containing one (SSite) or three (TriSite) proteolytic cleavage sites were engineered and conjugated to PEGDA macromers followed by photopolymerization to form PEGDA hydrogels with tethered cell adhesion ligands of YRGDS and with either single or multiple MMPsensitive peptide domains between cross links. These hydrogels were investigated as provisional matrices for inducing neovascularization, while maintaining the structural integrity of the hydrogel network. We show that hydrogels made from SSite and TriSite peptide-containing PEGDA macromers polymerized under the same conditions do not result in alterations in hydrogel swelling, mesh size, or compressive modulus, but result in statistically different hydrogel degradation times with TriSite gels degrading in 1-3 h compared to 2-4 days in SSite gels. In both polymer types, increases in the PEGDA concentration result in decreases in hydrogel swelling and mesh size, and increases in the compressive modulus and degradation time. Furthermore, TriSite gels support vessel invasion over a 0.3-3.6 kPa range of compressive modulus, while SSite gels do not support invasion in hydrogels above compressive modulus values of 0.4 kPa. In vitro data demonstrate that TriSite gels result in enhanced vessel invasion areas by sevenfold and depth of invasion by twofold compared to SSite gels by 3 weeks. This approach allows for controlled, localized, and cell-mediated matrix remodeling and can be tailored to tissues that may require more rapid regeneration and neovascularization.

Macromolecular Reaction Engineering, Feb 18, 2019

Polyphosphate salts, such as sodium hexametaphosphate (PPi), are effective in the attenuation of ... more Polyphosphate salts, such as sodium hexametaphosphate (PPi), are effective in the attenuation of collagenase and biofilm production and prevention of anastomotic leak in mice models. However, systemic administration of polyphosphate solutions to the gut presents a series of difficulties such as uncontrolled delivery to target and off-site tissues. In this article a process to produce PPi-loaded poly(ethylene glycol) diacrylate (PEGDA) hydrogel nanoparticles through miniemulsion polymerization is developed. The effects of using a polyphosphate salt, as compared to a monophosphate salt, is investigated through cloud point measurements, which is then translated to a change in the required HLB of the miniemulsion system. A parametric study is developed and yields a way to control particle swelling ratio and mean diameter based on the surfactant and/or initiator concentration, among other parameters. Finally, release kinetics of two different crosslink density particles shows a sustained and tunable release of the encapsulated polyphosphate.

Biomaterials Science, 2017

Peptides that mimic the bioactivity of growth factors are rapidly emerging as therapeutics for a ... more Peptides that mimic the bioactivity of growth factors are rapidly emerging as therapeutics for a variety of drug delivery applications including therapeutic neovascularization. Neovascularization requires controlled and sustained delivery of proangiogenic factors to stimulate reperfusion of ischemic tissues. To this end, hydrogel nanoparticles were designed to provide sustained and tunable diffusion-based release of a pro-angiogenic peptide, QK. Inverse phase mini-emulsion polymerization (IPMP) was used to generate crosslinked poly(ethylene) glycol (PEG) hydrogel nanoparticles entrapped with the QK peptide. Peptide release kinetics were tuned through adjustments in nanoparticle crosslink density. This was achieved by altering the mole fraction of the crosslinking agent which allowed for the synthesis of low crosslink density (0.754 mmol cm(-3)) and high crosslink density (0.810 mmol cm(-3)) nanoparticles. Nanoparticle tracking analysis revealed narrow particle size distributions and similar particle sizes regardless of crosslink density (225 ± 75 nm and 233 ± 73 nm, for low and high crosslink density nanoparticles, respectively). The zeta potential was found to be -26 mV for blank nanoparticles and +4 mV in the case of QK-loaded nanoparticles. The resulting nanoparticle crosslink density impacted both peptide loading as well as release kinetics. In terms of cumulative fractional release and weight of peptide released per mass of nanoparticle, higher crosslink density nanoparticles resulted in slower peptide release kinetics. The IPMP process preserved the QK secondary structure and its bioactivity as confirmed using circular dichroism spectroscopy and a Matrigel tubulogenesis assay, respectively, with released peptide. The presented nanoparticles hold great potential for use as drug delivery carriers for stimulation of therapeutic neovascularization of ischemic tissues.

Journal of Biomaterials Science-polymer Edition, 2012

The spatial presentation of soluble growth factors, immobilized extracellular matrix molecules, a... more The spatial presentation of soluble growth factors, immobilized extracellular matrix molecules, as well as matrix rigidity, plays an important role in directed and guided cell migration. Synthetic hydrogel scaffolds offer the ability to systematically introduce gradients of these factors contributing to our understanding of how the 3D arrangement of biochemical and mechanical cues influence cell behavior. Using a novel photopolymerization technique, perfusion-based frontal photopolymerization (PBFP), we have engineered poly(ethylene glycol) diacrylate (PEGDA) hydrogel scaffolds with gradients of mechanical properties and immobilized biofunctionality. The controlled delivery of a buoyant photoinitiator, eosin Y, through a glass frit filter results in the formation and subsequent propagation of a polymer reaction front that is self-sustained and able to propagate through the monomeric mixture. Propagation of this front results in monomer depletion, leading to variations in cross-linking, as well as spatial gradients of elastic modulus and immobilized concentrations of the YRGDS cell adhesion ligand within PEGDA hydrogels. Furthermore, the magnitudes of the resulting gradients are controlled through alterations in polymerization conditions. Preliminary in vitro cell-culture studies demonstrate that the gradients generated stimulate directed 2D cell growth on the surface of PEGDA hydrogels. By day 14, fibroblast aggregates spread roughly twice as far in the direction parallel to the slope of the gradient as compared to the perpendicular direction. The presented technique has great potential in controlling gradients of mechanical properties and immobilized biofunctionality for directing and guiding 3D cell behavior within tissue-engineered scaffolds.

Macromolecular Theory and Simulations, Sep 1, 2003

Macromolecular Bioscience, Jan 20, 2014

Proteolytically degradable poly(ethylene) glycol (PEG) hydrogels have been investigated as tissue... more Proteolytically degradable poly(ethylene) glycol (PEG) hydrogels have been investigated as tissue engineering scaffolds; however, cell invasion and tissue regeneration are limited by the rate of cell-mediated degradation due to the small mesh size of the resultant crosslinked network. Gelatin leaching is combined with photopolymerization to form porous matrixmetalloproteinase (MMP)-sensitive PEG scaffolds under cytocompatible conditions in the presence of cells. Gelatin leaching allows control over pore size and porosity through selectivity of gelatin bead particle size and porogen loading, respectively. Increases in porogen loading lead to increased porosity, decreased compressive modulus and degradation time, and enhanced proliferation of encapsulated vascular smooth muscle cells.

Journal of Investigative Medicine, Oct 1, 2010

Biocompatible, degradable, polymer scaffolds combined with cells or biological signals are being ... more Biocompatible, degradable, polymer scaffolds combined with cells or biological signals are being investigated as alternatives to traditional options for tissue reconstruction and transplantation. These approaches are already in clinical use as engineered tissues that enhance wound healing and skin regeneration. The continued enhancement of these material strategies is highly dependent on the ability to promote rapid and stable neovascularization (new blood vessel formation) within the scaffold. While neovascularization therapies have shown some promise for the treatment of ischemic tissues, vascularization of polymer scaffolds in tissue engineering strategies provide a unique challenge due to the volume and complexity of the tissues targeted. In this article we examine recent advances in research focused on promoting neovascularization in polymer scaffolds for tissue engineering applications. These approaches include the use of growth factors, cells, and novel surgical approaches to both enhance and control the nature of the vascular networks formed. The continued development of these approaches may lead to new tissue engineering strategies for the generation of skin and other tissues or organs.

PLOS ONE, Mar 12, 2013

The spatial presentation of immobilized extracellular matrix (ECM) cues and matrix mechanical pro... more The spatial presentation of immobilized extracellular matrix (ECM) cues and matrix mechanical properties play an important role in directed and guided cell behavior and neovascularization. The goal of this work was to explore whether gradients of elastic modulus, immobilized matrix metalloproteinase (MMP)-sensitivity, and YRGDS cell adhesion ligands are capable of directing 3D vascular sprout formation in tissue engineered scaffolds. PEGDA hydrogels were engineered with mechanical and biofunctional gradients using perfusion-based frontal photopolymerization (PBFP). Bulk photopolymerized hydrogels with uniform mechanical properties, degradation, and immobilized biofunctionality served as controls. Gradient hydrogels exhibited an 80.4% decrease in elastic modulus and a 56.2% decrease in immobilized YRGDS. PBFP hydrogels also demonstrated gradients in hydrogel degradation with degradation times ranging from 10-12 hours in the more crosslinked regions to 4-6 hours in less crosslinked regions. An in vitro model of neovascularization, composed of co-culture aggregates of endothelial and smooth muscle cells, was used to evaluate the effect of these gradients on vascular sprout formation. Aggregate invasion in gradient hydrogels occurred bi-directionally with sprout alignment observed in the direction parallel to the gradient while control hydrogels with homogeneous properties resulted in uniform invasion. In PBFP gradient hydrogels, aggregate sprout length was found to be twice as long in the direction parallel to the gradient as compared to the perpendicular direction after three weeks in culture. This directionality was found to be more prominent in gradient regions of increased stiffness, crosslinked MMP-sensitive peptide presentation, and immobilized YRGDS concentration.

Cardiovascular Pathology, May 1, 2013

Industrial & Engineering Chemistry Research, Feb 15, 2005

A bifurcation analysis for continuous nonlinear free-radical polymerization subject to gel format... more A bifurcation analysis for continuous nonlinear free-radical polymerization subject to gel formation is presented. The analysis uses the Numerical Fractionation technique and studies the multiplicity and dynamics of the sol and gel polymer properties for bulk, nonisothermal, vinyl-divinyl copolymerization. The bifurcation analysis has revealed s-shape, mushroom, and isola-type multiplicity structures; multiple critical gel transitions; and interesting dynamics for the system investigated.

Macromolecular Reaction Engineering, Nov 20, 2007

Biomacromolecules, Nov 30, 2020

In the early 1940s, Paul Flory and John Rehner published a series of papers on the properties of ... more In the early 1940s, Paul Flory and John Rehner published a series of papers on the properties of swellable polymeric networks. Originally intended for vulcanized rubber, their development has since been extensively used and extended to much more complex systems, such as hydrogels, and used to estimate the mesh size of such networks. In this article, we take a look at the development of the Flory−Rehner equation and highlight several issues that arise when using such a theory for the described hydrogel networks. We then propose a new approach and equations to accurately calculate the backbone molecular weight in-between crosslinks while explicitly accounting for the molecular mass of the crosslinker and branch segments. The approach also provides more applicable mesh dimensions, for complex networks with macromeric crosslinkers and/or a high degree of branching, as is the case of biocompatible hydrogels. The approach is finally illustrated by a case study comparing the values obtained with our proposed approach to those using the state-of-the-art approach.

Nanotechnology, Science and Applications, Apr 1, 2022

Background: Rotational manipulation of chains or clusters of magnetic nanoparticles (MNPs) offers... more Background: Rotational manipulation of chains or clusters of magnetic nanoparticles (MNPs) offers a means for directed translation and payload delivery that should be explored for clinical use. Multiple MNP types are available, yet few studies have performed sideby-side comparisons to evaluate characteristics such as velocity, movement at a distance, and capacity for drug conveyance or dispersion. Purpose: Our goal was to design, build, and study an electric device allowing simultaneous, multichannel testing (e.g., racing) of MNPs in response to a rotating magnetic field. We would then select the "best" MNP and use it with optimized device settings, to transport an unbound therapeutic agent. Methods: A magnetomotive system was constructed, with a Helmholtz pair of coils on either side of a single perpendicular coil, on top of which was placed an acrylic tray having multiple parallel lanes. Five different MNPs were tested: graphene-coated cobalt MNPs (TurboBeads™), nickel nanorods, gold-iron alloy MNPs, gold-coated Fe 3 O 4 MNPs, and uncoated Fe 3 O 4 MNPs. Velocities were determined in response to varying magnetic field frequencies (5-200 Hz) and heights (0-18 cm). Velocities were normalized to account for minor lane differences. Doxorubicin was chosen as the therapeutic agent, assayed using a CLARIOstar Plus microplate reader. Results: The MMS generated a maximal MNP velocity of 0.9 cm/s. All MNPs encountered a "critical" frequency at 20-30 Hz. Nickel nanorods had the optimal response based on tray height and were then shown to enable unbound doxorubicin dispersion along 10.5 cm in <30 sec. Conclusion: A rotating magnetic field can be conveniently generated using a three-coil electromagnetic device, and used to induce rotational and translational movement of MNP aggregates over mesoscale distances. The responses of various MNPs can be compared side-by-side using multichannel acrylic trays to assess suitability for drug delivery, highlighting their potential for further in vivo applications.

Biomacromolecules, Mar 17, 2023

In the early 1940s, Paul Flory and John Rehner published a series of papers on the properties of ... more In the early 1940s, Paul Flory and John Rehner published a series of papers on the properties of swellable polymeric networks. Originally intended for vulcanized rubber, their development has since been extensively used and extended to much more complex systems, such as hydrogels, and used to estimate the mesh size of such networks. In this article, we take a look at the development of the Flory−Rehner equation and highlight several issues that arise when using such a theory for the described hydrogel networks. We then propose a new approach and equations to accurately calculate the backbone molecular weight in-between crosslinks while explicitly accounting for the molecular mass of the crosslinker and branch segments. The approach also provides more applicable mesh dimensions, for complex networks with macromeric crosslinkers and/or a high degree of branching, as is the case of biocompatible hydrogels. The approach is finally illustrated by a case study comparing the values obtained with our proposed approach to those using the state-of-the-art approach.

Macromolecular Reaction Engineering, May 17, 2018

N-vinyl pyrrolidone (NVP) aqueous-phase polymerization is known to depend on the degree of hydrat... more N-vinyl pyrrolidone (NVP) aqueous-phase polymerization is known to depend on the degree of hydration of the NVP molecules, resulting in an increase in the rate of propagation with decreasing monomer concentration. When potassium monophosphate and sodium hexametaphosphate are added to the monomer solution the reaction kinetics slow down, with the degree of retardation being dependent on salt-to-monomer concentration ratio. Using polymerization reaction models in combination with ion coordination theory, this effect can be associated with an active interaction of the ions in solution with the NVP molecules. When varying the solution pH, an optimum operating zone ranging approximately from pH 4 to pH 7 for the NVP-V-50 2,2′-Azobis(2-methylpropionamidine) dihydrochloride (AAPH) system is found. Potassium persulfate is unable to initiate NVP homopolymerization. The addition of poly(ethylene glycol) diacrylate as a comonomer reduces the kinetic slowdown caused by the addition of salts or by extreme pH and significantly increases the overall conversion rate.

Journal of Biomedical Optics, Nov 8, 2019

Lymph node biopsy is a primary means of staging breast cancer, yet standard pathological techniqu... more Lymph node biopsy is a primary means of staging breast cancer, yet standard pathological techniques are time-consuming and typically sample less than 1% of the total node volume. A low-cost fluorescence optical projection tomography (OPT) protocol is demonstrated for rapid imaging of whole lymph nodes in three dimensions. The relatively low scattering properties of lymph node tissue can be leveraged to significantly improve spatial resolution of lymph node OPT by employing angular restriction of photon detection. It is demonstrated through porcine lymph node metastases models that simple filtered-backprojection reconstruction is sufficient to detect and localize 200-μm-diameter metastases (the smallest clinically significant) in 1-cm-diameter lymph nodes. © The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.

Macromolecular Reaction Engineering, Nov 15, 2013

PEGDA hydrogels copolymerized with NVP using free‐radical photopolymerization are used in biomedi... more PEGDA hydrogels copolymerized with NVP using free‐radical photopolymerization are used in biomedical applications. These networks consist of a poly(acrylate‐co‐vinyl pyrrolidone) backbone crosslinked with PEG chains whose crosslink density is dependent on the backbone molecular weight and composition. Insight into the network structure and characterization of the backbone molecular weight and composition is achieved by considering hydrogel degradation through ester bond hydrolysis resulting in the release of PEG and poly(acrylic acid‐co‐vinyl pyrrolidone). A model is developed to determine the influence of kinetic constants and phenomena on the backbone formation and is compared to experimental data. Results indicate that the backbone molecular weight is related to the amount of NVP and unaffected by polymerization time.

Acta Biomaterialia, Jul 1, 2012

Controlled scaffold degradation is a critical design criterion for the clinical success of tissue... more Controlled scaffold degradation is a critical design criterion for the clinical success of tissue engineered constructs. Here, we exploited a biomimetic poly(ethylene glycol) diacrylate (PEGDA) hydrogel system immobilized with tethered YRGDS as the cell adhesion ligand and with either single (SSite) or multiple (MSite) collagenase-sensitive domains between crosslinks, to systematically study the effect of proteolytic cleavage site presentation on hydrogel degradation rate and 3D fibroblast invasion in vitro. Through the incorporation of multiple collagenasesensitive domains between crosslinks, hydrogel degradation rate was controlled and enhanced independent of alterations in compressive modulus. As compared to SSite hydrogels, MSite hydrogels resulted in increased 3D fibroblast invasion in vitro which occurred over a wider range of compressive modulus. Furthermore, encapsulated soluble acidic fibroblast growth factor (FGF-1), a potent mitogen during processes such as vascularization and wound healing, was incorporated into SSite and MSite PEGDA scaffolds to determine its in vitro potential on fibroblast cell invasion. Hydrogels containing soluble FGF-1 significantly enhanced 3D fibroblast invasion in a dose-dependent manner within the different types of PEG matrices investigated over a period of 15 days. The methodology presented provides flexibility in designing PEG scaffolds with desired mechanical properties, but with increased susceptibility to proteolytically-mediated degradation. These results indicate that effective tuning of initial matrix stiffness and hydrogel degradation kinetics plays a critical role in effectively designing PEG scaffolds that promote controlled 3D cellular behavior and in situ tissue regeneration.

Biomaterials Science, Jul 7, 2014

Controlled vascular response in scaffolds following implantation remains a significant clinical c... more Controlled vascular response in scaffolds following implantation remains a significant clinical challenge. A critical biomaterial design criterion is the synchronization of the rates of scaffold degradation and vascularized tissue formation. Matrix metalloproteinases (MMPs) are key enzymes that regulate neovascularization and extracellular matrix remodelling. Synthetic proteasesensitive hydrogels offer controllable environments for investigating the role of matrix degradation on neovascularization. In this study, PEG hydrogels containing MMP-sensitive peptides with increased catalytic activity for MMPs expressed during neovascularization were investigated. Scaffolds were functionalized with MMP-2-, MMP-14-or general collagenase-sensitive peptides and with varying peptide concentration using crosslinkers containing one (SSite) or multiple (TSite) repeats of each protease-sensitive sequence. Increasing peptide concentration enhanced the degradation kinetics of scaffolds functionalized with MMP-specific sequences while 80% of the collagenase-sensitive scaffolds remained upon exposure to MMP-2 and MMP-14. In vitro neovascularization was consistent with in vivo tissue invasion with significantly increased invasion occurring within SSite MMP-specific as compared to collagenase-sensitive hydrogels and with further invasion in TSite as compared to SSite hydrogels regardless of peptide specificity. All scaffolds supported in vivo neovascularization; however, this was not dependent on peptide specificity. These findings demonstrate that peptide concentration and specificity regulate in vivo scaffold degradation, neovascularization and matrix remodelling.

Tissue Engineering Part A, Dec 1, 2012

The volume of tissue that can be engineered is limited by the extent to which vascularization can... more The volume of tissue that can be engineered is limited by the extent to which vascularization can be stimulated within the scaffold. The ability of a scaffold to induce vascularization is highly dependent on its rate of degradation. We present a novel approach for engineering poly (ethylene glycol) diacrylate (PEGDA) hydrogels with controlled protease-mediated degradation independent of alterations in hydrogel mechanical and physical properties. Matrix metalloproteinase (MMP)-sensitive peptides containing one (SSite) or three (TriSite) proteolytic cleavage sites were engineered and conjugated to PEGDA macromers followed by photopolymerization to form PEGDA hydrogels with tethered cell adhesion ligands of YRGDS and with either single or multiple MMPsensitive peptide domains between cross links. These hydrogels were investigated as provisional matrices for inducing neovascularization, while maintaining the structural integrity of the hydrogel network. We show that hydrogels made from SSite and TriSite peptide-containing PEGDA macromers polymerized under the same conditions do not result in alterations in hydrogel swelling, mesh size, or compressive modulus, but result in statistically different hydrogel degradation times with TriSite gels degrading in 1-3 h compared to 2-4 days in SSite gels. In both polymer types, increases in the PEGDA concentration result in decreases in hydrogel swelling and mesh size, and increases in the compressive modulus and degradation time. Furthermore, TriSite gels support vessel invasion over a 0.3-3.6 kPa range of compressive modulus, while SSite gels do not support invasion in hydrogels above compressive modulus values of 0.4 kPa. In vitro data demonstrate that TriSite gels result in enhanced vessel invasion areas by sevenfold and depth of invasion by twofold compared to SSite gels by 3 weeks. This approach allows for controlled, localized, and cell-mediated matrix remodeling and can be tailored to tissues that may require more rapid regeneration and neovascularization.

Macromolecular Reaction Engineering, Feb 18, 2019

Polyphosphate salts, such as sodium hexametaphosphate (PPi), are effective in the attenuation of ... more Polyphosphate salts, such as sodium hexametaphosphate (PPi), are effective in the attenuation of collagenase and biofilm production and prevention of anastomotic leak in mice models. However, systemic administration of polyphosphate solutions to the gut presents a series of difficulties such as uncontrolled delivery to target and off-site tissues. In this article a process to produce PPi-loaded poly(ethylene glycol) diacrylate (PEGDA) hydrogel nanoparticles through miniemulsion polymerization is developed. The effects of using a polyphosphate salt, as compared to a monophosphate salt, is investigated through cloud point measurements, which is then translated to a change in the required HLB of the miniemulsion system. A parametric study is developed and yields a way to control particle swelling ratio and mean diameter based on the surfactant and/or initiator concentration, among other parameters. Finally, release kinetics of two different crosslink density particles shows a sustained and tunable release of the encapsulated polyphosphate.

Biomaterials Science, 2017

Peptides that mimic the bioactivity of growth factors are rapidly emerging as therapeutics for a ... more Peptides that mimic the bioactivity of growth factors are rapidly emerging as therapeutics for a variety of drug delivery applications including therapeutic neovascularization. Neovascularization requires controlled and sustained delivery of proangiogenic factors to stimulate reperfusion of ischemic tissues. To this end, hydrogel nanoparticles were designed to provide sustained and tunable diffusion-based release of a pro-angiogenic peptide, QK. Inverse phase mini-emulsion polymerization (IPMP) was used to generate crosslinked poly(ethylene) glycol (PEG) hydrogel nanoparticles entrapped with the QK peptide. Peptide release kinetics were tuned through adjustments in nanoparticle crosslink density. This was achieved by altering the mole fraction of the crosslinking agent which allowed for the synthesis of low crosslink density (0.754 mmol cm(-3)) and high crosslink density (0.810 mmol cm(-3)) nanoparticles. Nanoparticle tracking analysis revealed narrow particle size distributions and similar particle sizes regardless of crosslink density (225 ± 75 nm and 233 ± 73 nm, for low and high crosslink density nanoparticles, respectively). The zeta potential was found to be -26 mV for blank nanoparticles and +4 mV in the case of QK-loaded nanoparticles. The resulting nanoparticle crosslink density impacted both peptide loading as well as release kinetics. In terms of cumulative fractional release and weight of peptide released per mass of nanoparticle, higher crosslink density nanoparticles resulted in slower peptide release kinetics. The IPMP process preserved the QK secondary structure and its bioactivity as confirmed using circular dichroism spectroscopy and a Matrigel tubulogenesis assay, respectively, with released peptide. The presented nanoparticles hold great potential for use as drug delivery carriers for stimulation of therapeutic neovascularization of ischemic tissues.

Journal of Biomaterials Science-polymer Edition, 2012

The spatial presentation of soluble growth factors, immobilized extracellular matrix molecules, a... more The spatial presentation of soluble growth factors, immobilized extracellular matrix molecules, as well as matrix rigidity, plays an important role in directed and guided cell migration. Synthetic hydrogel scaffolds offer the ability to systematically introduce gradients of these factors contributing to our understanding of how the 3D arrangement of biochemical and mechanical cues influence cell behavior. Using a novel photopolymerization technique, perfusion-based frontal photopolymerization (PBFP), we have engineered poly(ethylene glycol) diacrylate (PEGDA) hydrogel scaffolds with gradients of mechanical properties and immobilized biofunctionality. The controlled delivery of a buoyant photoinitiator, eosin Y, through a glass frit filter results in the formation and subsequent propagation of a polymer reaction front that is self-sustained and able to propagate through the monomeric mixture. Propagation of this front results in monomer depletion, leading to variations in cross-linking, as well as spatial gradients of elastic modulus and immobilized concentrations of the YRGDS cell adhesion ligand within PEGDA hydrogels. Furthermore, the magnitudes of the resulting gradients are controlled through alterations in polymerization conditions. Preliminary in vitro cell-culture studies demonstrate that the gradients generated stimulate directed 2D cell growth on the surface of PEGDA hydrogels. By day 14, fibroblast aggregates spread roughly twice as far in the direction parallel to the slope of the gradient as compared to the perpendicular direction. The presented technique has great potential in controlling gradients of mechanical properties and immobilized biofunctionality for directing and guiding 3D cell behavior within tissue-engineered scaffolds.

Macromolecular Theory and Simulations, Sep 1, 2003

Macromolecular Bioscience, Jan 20, 2014

Proteolytically degradable poly(ethylene) glycol (PEG) hydrogels have been investigated as tissue... more Proteolytically degradable poly(ethylene) glycol (PEG) hydrogels have been investigated as tissue engineering scaffolds; however, cell invasion and tissue regeneration are limited by the rate of cell-mediated degradation due to the small mesh size of the resultant crosslinked network. Gelatin leaching is combined with photopolymerization to form porous matrixmetalloproteinase (MMP)-sensitive PEG scaffolds under cytocompatible conditions in the presence of cells. Gelatin leaching allows control over pore size and porosity through selectivity of gelatin bead particle size and porogen loading, respectively. Increases in porogen loading lead to increased porosity, decreased compressive modulus and degradation time, and enhanced proliferation of encapsulated vascular smooth muscle cells.

Journal of Investigative Medicine, Oct 1, 2010

Biocompatible, degradable, polymer scaffolds combined with cells or biological signals are being ... more Biocompatible, degradable, polymer scaffolds combined with cells or biological signals are being investigated as alternatives to traditional options for tissue reconstruction and transplantation. These approaches are already in clinical use as engineered tissues that enhance wound healing and skin regeneration. The continued enhancement of these material strategies is highly dependent on the ability to promote rapid and stable neovascularization (new blood vessel formation) within the scaffold. While neovascularization therapies have shown some promise for the treatment of ischemic tissues, vascularization of polymer scaffolds in tissue engineering strategies provide a unique challenge due to the volume and complexity of the tissues targeted. In this article we examine recent advances in research focused on promoting neovascularization in polymer scaffolds for tissue engineering applications. These approaches include the use of growth factors, cells, and novel surgical approaches to both enhance and control the nature of the vascular networks formed. The continued development of these approaches may lead to new tissue engineering strategies for the generation of skin and other tissues or organs.

PLOS ONE, Mar 12, 2013

The spatial presentation of immobilized extracellular matrix (ECM) cues and matrix mechanical pro... more The spatial presentation of immobilized extracellular matrix (ECM) cues and matrix mechanical properties play an important role in directed and guided cell behavior and neovascularization. The goal of this work was to explore whether gradients of elastic modulus, immobilized matrix metalloproteinase (MMP)-sensitivity, and YRGDS cell adhesion ligands are capable of directing 3D vascular sprout formation in tissue engineered scaffolds. PEGDA hydrogels were engineered with mechanical and biofunctional gradients using perfusion-based frontal photopolymerization (PBFP). Bulk photopolymerized hydrogels with uniform mechanical properties, degradation, and immobilized biofunctionality served as controls. Gradient hydrogels exhibited an 80.4% decrease in elastic modulus and a 56.2% decrease in immobilized YRGDS. PBFP hydrogels also demonstrated gradients in hydrogel degradation with degradation times ranging from 10-12 hours in the more crosslinked regions to 4-6 hours in less crosslinked regions. An in vitro model of neovascularization, composed of co-culture aggregates of endothelial and smooth muscle cells, was used to evaluate the effect of these gradients on vascular sprout formation. Aggregate invasion in gradient hydrogels occurred bi-directionally with sprout alignment observed in the direction parallel to the gradient while control hydrogels with homogeneous properties resulted in uniform invasion. In PBFP gradient hydrogels, aggregate sprout length was found to be twice as long in the direction parallel to the gradient as compared to the perpendicular direction after three weeks in culture. This directionality was found to be more prominent in gradient regions of increased stiffness, crosslinked MMP-sensitive peptide presentation, and immobilized YRGDS concentration.

Cardiovascular Pathology, May 1, 2013

Industrial & Engineering Chemistry Research, Feb 15, 2005

A bifurcation analysis for continuous nonlinear free-radical polymerization subject to gel format... more A bifurcation analysis for continuous nonlinear free-radical polymerization subject to gel formation is presented. The analysis uses the Numerical Fractionation technique and studies the multiplicity and dynamics of the sol and gel polymer properties for bulk, nonisothermal, vinyl-divinyl copolymerization. The bifurcation analysis has revealed s-shape, mushroom, and isola-type multiplicity structures; multiple critical gel transitions; and interesting dynamics for the system investigated.

Macromolecular Reaction Engineering, Nov 20, 2007